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2000 Progress Report: Effects of an Endocrine Disruptor on Prostate Development and GrowthEPA Grant Number: R827403
Title: Effects of an Endocrine Disruptor on Prostate Development and Growth
Investigators: Timms, Barry G.
Institution: University of South Dakota
EPA Project Officer: Saint, Chris
Project Period: July 1, 1999 through June 30, 2002
Project Period Covered by this Report: July 1, 1999 through June 30, 2000
Project Amount: $432,452
RFA: Endocrine Disruptors (1999) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Endocrine Disruptors , Health , Safer Chemicals
Our long-term goal is to determine the consequences of exposure to endocrine disrupters during fetal prostate development, particularly environmental estrogens. The goal of the proposed experiments is to understand the mechanisms associated with our initial finding of dose-dependent effects on prostate growth, as a result of fetal exposure to environmental chemicals. Specifically, we will examine regional growth effects in the urogenital sinus (UGS) following exposure of mouse fetuses to a low, physiologically relevant dose of the pesticide, methoxychlor (MXC). By comparison, the effects of a high dose of MXC will be examined and compared to diethylstilbestrol (DES) treatment as a positive control. Progress Summary:
The initial 6-month period of the study was used to prepare the laboratory environment for the program of study, establish protocols and hire personnel.
The plan for the first year was to address the first specific aim of the project and study the effects of prenatal exposure to environmental estrogens on ductal budding patterns and morphometry in the developing prostate of male mice. Control and DES positive control-treated groups have been analyzed and the preliminary findings are summarized below.
Pregnant female CD-1 mice were fed oil (control) or oil plus DES (0.1 µg/kg) on gestation days 14-18. Caesarian delivery was performed on day 19. To preclude intrauterine position effects, one 1M male per litter was used for the studies. A total of five animals were taken for each group. The urogenital complex was fixed in situ, according to previously published protocols. Serial sections were prepared on coded samples. Morphometric analysis was performed to provide data on number of buds and 3D reconstruction for the control and positive control (DES) treated animals (Figure1).
A. Surface-rendered reconstruction of control, 19-day male fetus (1M - dorsolateral view).
B. Surface-rendered reconstruction of DES-treated (0.1 µg/kg), 19-day male fetus (1M - dorsolateral view). Urethra (red); dorsocranial gland (dark blue); dorsal prostate (green); lateral prostate (yellow); ventral prostate (pale blue).
While the budding data have not typically shown highly significant differences, our experience with another positive control (ethinyl estradiol), and an endocrine disrupter (bisphenol A), indicate that the mean cross-sectional area measurement (an indicator of volume) is correlated with a more significant growth effect (vom Saal, et al., 2000; Kaiser, 2000).
The reconstruction data for the high dose DES positive control indicate that this dose range results in abnormal urogenital sinus development in some animals. In these instances, where portions of the Mullerian system are retained, there is an inhibition of dorsal prostate budding, while lateral and ventral buds are observed. In all cases examined thus far, the effects of higher physiological doses of estrogen result in an overall decrease in the number of prostatic outgrowths, except for the ventral region.
The preliminary data suggest that these morphological growth parameters should provide useful information about prostate development when we examine the effects of MXC treatment during fetal development. Based upon published and current preliminary data, it is postulated that low, physiologically relevant (i.e. endocrine disruption), during critical periods of reproductive development in the male fetus, are likely to cause alterations of growth parameters.
Kaiser J. Endocrine disrupters: panel cautiously confirms low-dose effects.
We plan to complete the fetal treatment groups for the reconstruction analyses during the subsequent grant period. Additional animals will be treated and examined after puberty and maturation to examine the long-term consequences on prostate growth and development of fetal exposure to endocrine disrupters. Journal Articles:
No journal articles submitted with this report: View all 11 publications for this projectSupplemental Keywords:
health effects, dose-response, mammalian, cellular, chemicals, histology, prostate development., RFA, Health, Scientific Discipline, Toxics, Ecology, Environmental Chemistry, Health Risk Assessment, Chemistry, pesticides, Endocrine Disruptors - Environmental Exposure & Risk, endocrine disruptors, Risk Assessments, Children's Health, Biology, Endocrine Disruptors - Human Health, morphological biomarkers, childhood development, ductal budding patterns, dose response, endocrine disrupting chemicals, steroid, Methoxychlor, developmental biology, animal models, human exposure, fetal development, cellular growth, prostate cancer